HIV-TB co-infection: overview

and recent update

Brian Eley

Paediatric Infectious Diseases Unit

Red Cross War Memorial Children’s Hospital

School of Child and Adolescent Health

University of Cape Town

HIV prevalence in patients with TB

http://www.who.int/tb/publications/global_report/2009/pdf/full_report.pdf

Madhi SA, et al. Int J Tuberc Lung Dis 2000;4(5):448-454

Kiwanuka J, et al. Ann Trop Paediatr 2001;21:5-14

Jeena P, et al. Int Tub ercJ Lung Dis 2002;6(8):672-678

Schaaf HS, et al. BMC Infect Dis 2007;7:140

Paediatric studies: HIV prevalence in TBMadhi S, et al. (2000): 68/161 [42%]

Kiwanuka, et al. (2001): 72/102 [70.6%]

Jeena P, et al. (2002): 57/118 [48%]

Schaaf S, et al: (2007): 133/414 [32.1%]

TB risk in HIV-infected children

Hesseling A, et al. Clin Infect Dis 2009;48:108-114

Effect of cART on TB risk

Ref Design TB incidence rate / TB risk

1 Cohort

(n=1132)

SA

Pre-cART: 21.1 / 100 py vs on cART: 6.4 / 100 py a crude

reduction of 70%

2 Cohort

(n=6535)

DRC

On cART: 7.2 / 100 py vs not on-cART: 22.2 / 1– py; IRR for

cART = 0.32 [0.26-0.40]

Adjusted for other factors, cART was associated with

marked reduction in TB risk; AHR: 0.15 [0.12-0.20]

3 Cohort

(n=364)

Kenya

On-cART: 10.2 / 100 py vs not on-cART: 20.4 / 100 py

Model-estimated TB Hazard ratio for cART: 0.51 [0.27-0.94]

• Reconstitution of specific antimycobacterial immunityKampmann B, et al. AIDS 2006; 20:1011-1018

Tena-Coki N, et al. Am J Respir Crit Care Med 2010 Mar 11. [Epub ahead of print]

1 Martinson NA, et al. Int J Tuberc Lung Dis 2009;13(7):862-867; 2 Braitstein P et al. P Infect dis J 2009;28:626-6323 Edmonds A, et al. Int J Epidemiol 2009;38:1612-1621

Approach to TB diagnosis

• History (Contact, symptoms consistent with TB)

• Clinical examination (including growth

assessment)

• Tuberculin skin testing

• Bacteriological confirmation whenever possible

• Investigations relevant for suspected PTB and

EPTB

• Scoring systems

• HIV testing (in high prevalence areas)

WHO, WHO/HTM/TB/2006.361, 2006

Diagnostic certainty

Definite TB Isolation of Mycobacterium tuberculosis on culture of sputum,

gastric washings, CSF or tissue from a site that is normally

sterile e.g. bone marrow, lymph node or other tissue

Probable TB Symptoms or signs consistent with TB plus two or more of the

following: known TB contact, TST 10mm, acid fast bacilli on

microscopy, chest radiograph findings consistent with PTB or

CSF findings CT scan findings consistent with TBM, and a

good response to treatment

Possible TB Symptoms or signs consistent with TB plus one of the

following: known TB contact, TST 10mm, chest radiograph

findings consistent with PTB or CSF findings CT scan

findings consistent with TBM, and a good response to

treatment

Impact of HIV on TB diagnosis

History including contact history NB because of poor sensitivity of TST

Symptoms consistent with TB Lower specificity due to overlap between

symptoms of TB & HIV

High proportion of patients with short

duration of symptoms

Examination including growth Lower specificity because malnutrition

common in TB & HIV

Tuberculin skin testing Lower sensitivity; TST positivity with

immunosuppression

Bacteriological confirmation Important but beyond capabilities of

many clinicians

Lacks sensitivity

Investigations relevant for

suspected PTB and EPTB

Wide range of diagnostic possibilities

because of other HIV-related disease

Chest radiograph findings Lower specificity: overlap with HIV-

related disease

Adapted from: WHO & IUATBLD, Guidance for national tuberculosis & HIV programmes, 2010 (near-final draft)

Culture-confirmed TB

Interferon- release assays (IGRAs)Reference Results

Liebeschuetz

(2004)

HIV-infected with confirmed/probable TB:

HIV-: 88/103 [85%] ELISPOT+ vs 64/91 [70%] TST+

HIV+: 22/30 [73%] ELISPOT+ vs 9/25 [36%] TST+

Davies (2009) HIV-infected with confirmed/probable TB:

HIV+: 25/39 [64%] ELISPOT+ vs 10/34 [29%] TST+

Limitations•Expense

• ‘Rule-in’ vs ‘rule-out’

•ELISPOT & Quantiferon assays produce discordant results

•In the absence of clinical & radiological signs IGRAs do not distinguish

between latent TB infection and active disease

•Discordance between TST and In vitro assays suggest that these are

complementary measures of antimycobacterial immunity

•Minimal study of the kinetics of IGRA responses in HIV-infected children

Liebeschuetz S, et al. Lancet 2004;364:2196

Davies M, et al. AIDS 2009;23:961-969

Mandalakas AM, et al. Int J Tuberc Lung Dis 2008;12;417-423

Gallant CJ, et al. Chest 2010;137:1071-1077

Connell TG, et al. BMC Infect Dis 2010;10:138

Newer (potential) diagnostic testsMicroscopic visualisation of bacteria: FM, LED & Bleach microscopy

Automated liquid culture systems: BACTEC MIGIT 960, ALERT 3D

Microscopic-observation drug-susceptibility (MODS) assay

Nucleic acid amplification tests (NAAT): loop-medicated isothermal

amplification (TB-LAMP), test, GenoType MTBDRplus assay, Geno Type

MTBDRsl, Inno-LiPA Rif TB Line probe assay, GeneXpert MTB

Antigen detection tests: LAM ELISA urinary antigen test

Antibody detection (serological) assays

Experimental approaches: host proteomic & gene expression signatures, TB

protein arrays

Perkins MD, et al. J Infect Dis 2007;196(Supp 1):S15-S27

Pai M, et al. Sem Respir Crit Care med 2008;29:560-568

Swaminthan S et al. Clin Infect Dis 2010;50(S3):S184-S194

Wallis RS, et al. Lancet 2010;375:1920-1937

Lawn , et al. AIDS 2009;23:1875-1880

HIV testing rates in TB patients

http://www.who.int/tb/publications/global_report/2009/pdf/full_report.pdf

Recommended TB regimens

TB disease Regimen

Intensive phase Continuation phase

New smear-negative PTB 2HRZ 4HR

Less severe forms EPTB [LN

disease, pl effusion]

2HRZ 4HR

New smear positive PTB with

extensive parenchymal involvement

2HRZE 4HR

Severe concomitant HIV infection 2HRZE 4HR

TB meningitis 6 HRZEo [Double the standard doses]

H=Isoniazid, R=rifampicin, Z=pyrazinamide, E=ethambutol, Eo=ethionamide

WHO, WHO/HTM/TB/2006.361, 2006

National ART Guidelines 2010

Preventive therapy • Routine TB prophylaxis for HIV-infected children is not

recommended

• All HIV-infected children, regardless of age should receive

INH x 6 months if exposed to close adult contact with PTB

• In the source case is resistant to INH, rifampicin 10-15

mg/kg/day should be administered for 4 months

ART & concomitant

TB

• If a child in on EFV, do not change the ARVs and add

standard TB therapy

• If the child is on LPV/r add additional RTV at a dose of 0.75

x the volume of the LPV/r dose

• In older children taking LPV/r the dose may be doubled

to roughly 600 mg/m2 of LPV (this is similar to the adult

guidelines)

• If the child in on NVP, ALT must be monitored. If

hepatitis develops refer to an expert

• If the child is unable to tolerate the large number of tablets,

ART should be interrupted until TB therapy has been

completed

National Department of Health. Guidelines for the Management of HIV in Children, 2nd Edition, 2010

Double dose LPV/r and rifampicin co-

treatment in children

Variable TB/HIV controls p value

Male : Female 4:11 16:8 0.015

Age (years) 1.25 (1.03,2.08) 1.59 (1.15,2.23) 0.603

Weight (kg) 8.8 (7.0,10.3) 10.6 (8.4,12.6) 0.015

BSA (m2) 0.43 (0.36,0.48) 0.48 (0.40,0.54) 0.022

Cpre (mg/L) 0.63(0.11,1.62) 4.25(3.42,8.10) 0.0001

Cmax (mg/L) 4.45(2.51, 8.22) 7.94(6.86,13.4) 0.006

AUC0-8h (mg.h/L) 22.29(13.78,65.50) 48.33(40.78,86.56) 0.013

McIlleron H, et al. CROI, February 2009

NVP and rifampicin co-treatment

• Thai study (n=8); mean age (range): 9.7 (4.4 – 11.8) yrs;

dosing with FDC (upper end NVP dose range: 150-220

mg/m2/dose) resulted in appropriate NVP exposure1

• Ugandan study (n=20; 7 on anti-TB Rx) mean age

(range): 5.0 (1.2 – 11.3) yrs : Only 3/7 (43%) on FDC

plus TB medication achieved adequate NVP trough level

> 3 mg/L2

• Zambian study (n=21);median age (range): 1.55 (0.66 –

3.18) yrs; mean daily dose 353 mg/m2; median (range)

pre-dose concentration (C0): 2.93 (1.06-11.4)mg/L; C0

<3.0 mg/L in 57%of children with TB and in 0% of

children without TB3

1 Prasitsuebsai W, et al. 16th CROI, poster 908, Montreal, February 2009 2 Barlow-Mosha L, et al. 16th CROI, poster 909, Montreal, February 20093 Oudijk JM, et al. 5th IAS Conference, Cape Town, 2009, LBPEB10

New Global Treatment

Guidelines and Research Gaps

WHO Recommendations, 2010Infants and children diagnosed with TB & HIV Strength of

recommendation

Quality of

evidence

Any child with active TB disease should begin TB treatment

immediately, and start ART as soon as tolerated in the first 8 weeks of

TB therapy, irrespective of CD4 count and clinical stage

Strong Very low

The preferred first-line ART regimen for infants & children < 3 years of age

who are taking a rifampicin-containing regimen for TB is 2 NRTIs + NVP or

a triple nucleoside regimen

Conditional Very low

The preferred first-line ART regimen for children > 3 years of age who

are taking a rifampicin-containing regimen for TB is 2 NRTIs + EFV

Conditional Very low

The preferred first-line ART regimen for infants < 2 years of age who have

been exposed to NVP and are taking a rifampicin-containing regimen for TB

is a triple NRTI regimen

Conditional Very low

HIV-infected infants & children who develop TB on ART

For all children, anti-TB therapy should be started immediately upon the

diagnosis of TB; ART should continue

Conditional Very low

Make adjustments to ART regimens as needed to decrease the potential

for toxicities and dug interactions;

•If on a regimen of 2 NRTIs + NVP, substitute EFV for NVP if child is ≥ 3

years

•If on a regimen of 2 NRTIs + NVP and substitution with EFV is not

possible, increase NVP to maximum dose

•If on a regimen containing LPV/r, consider adding RTV to 1:1 ratio

LPV:RVT to achieve full therapeutic dose

WHO, ART guidelines, 2010 revision ;http://whqlibdoc.who.int/publications/2010/9789241599801_eng.pdf

Children with HIV & TB

• Start TB therapy & ART within 8 weeks

– ART in HIV-TB coinfected adults mortality risk by

64-95%1

– Mortality rate 4-fold and TB rate 2-fold in patients

on deferred vs early ART2

– Mortality associated with IRIS is low3

– Recent observational data in children support this

guideline4

1 Harries AD, et al. Lancet 2010;375:1906-19192 Fitzgereald D. 5th IAS conference, Cape Town, July 2009; WESY201

3 Castelnuovo B, et al. Clin Infect Dis 2009;49:965-9724 Yotebieng M et al. AIDS 2010;24:1341-1349

Children with HIV & TB (2)

• 1st line ART > 3 yrs: 2 NRTIs + EFV– South Africa: Cmin < 1 mg/ml in 50% on Std. EFV

doses1,2

– EFV Cmin was similar during and after TB medication2

– Burkina Faso: 9/48 (19%) had Cmin < 1 mg/ml; 8/9 < 15 kg representing 44% of all children < 15 kg3

– Thailand: 8/63 (13%) had [EFV] < 1 mg/ml (measured 12-16 hrs after last dose); no correlation between [EFV] and virological response4

– Revised doses proposed, based on West African results3

– WHO revised doses in latest guidelines5

1 Ren Y, et al. JAIDS 2007;45(2):133-1362 Ren Y, et al. JAIDS 2009;50(5):439-4433 Hirt D, et al. Antimicrob Agents Chemother 2009;53:4407-4413

4 Puthanakit T, et al. Antivir Ther 2009;14:315-3205 http://whqlibdoc.who.int/publications/2010/9789241599801_eng.pdf

Children with HIV & TB (3)

• LPV/r-based regimens during TB treatment– Adults studies: Boosted LPV/r or double dose LPV/r may

overcome the effects of rifampicin on LPV metabolism1

– LPV/r boosted with additional RTV maintained LPV Cmin > 1 mg/ml in 13/15 children aged 7 mo -3.9 yrs2

– No data on boosted LPV/r in children aged < 6 months

– Double-dose LPV/r results in sub-optimal [LPV]: pre-dose [LPV] reduced in 80% of children with TB and 12/20 (60%) had Cmin < 1 mg/ml3

– Boosted LPV/r associated with good 6 & 12 months VL outcomes4

– WHO recommendation: RTV 50 mg heat stable sprinkle / tablet5

1 La Porte CJL, et al. Antimicrob Agents Chemother 2004;48:1553-15602 Ren Y, et al. J Acquir Immune Defic Syndr 2008;47:566-5693 McIlleron H, et al. 2010 (submitted)

4 Moodley M, et al. 17th CROI 2010, paper #1605 http://whqlibdoc.who.int/publications/2010/9789241599801_eng.pdf

Optimal dosages of TB drugs

• Isoniazid1

– Study: n=56, 22 (39%) HIV+, median age: 3.22 (IQR: 1.58-5.38) years

– At a dose of 4-6 mg/kg/day: Cmax was < 3mg/L in 70% of children

– At a dose of 8-12 mg/kg/day: All children achieved a Cmax > 3mg/L

– Multivariate analysis: NAT2 genotype but not age, sex or HIV status

was associated with Cmax

• Rifampicin2

– Prospective study: 21 HIV+ children – mean age: 3.73 yrs and 33 HIV-

children – mean age 4.05 yrs

– Mean dose of 9.61 mg/kg: 2-hour rifampicin concentrations were 3.9

and 4.8 l/ml in HIV+ and HIV- children respectively

– After 4 months of treatment: 3(6%) had 2-hour RMP concentration >8

l/ml and 25 (43%) were < 4 l/ml

1 McIlleron H, et al. Clin Infect Dis 2009;48:1547-15532 Schaaf S, et al. BMC Med 2009;7:19

WHO daily recommended dosages

Drug 2006

Daily dosage in mg/kg

Range (maximum)

2010

Daily dosage in mg/kg

Range (maximum)

Isoniazid 4 - 6 (300 mg) 10 – 15 (300 mg)

Rifampicin 8 -12 (600 mg) 10 – 20 (600 mg)

Pyrazinamide 20 - 30 30 – 40 (2000 mg)

Ethambutol Children: 15 – 25

Adults: 15 – 20

15 – 25 (1200 mg)

Streptomycin 12 - 18 12 – 18 (1000 mg)

WHO, WHO/HTM/TB/2006.361, 2006

WHO & IUATBLD, Guidance for national tuberculosis & HIV programmes, 2010 (near-final draft)

Duration of TB treatment20061 •6-month regimen recommended

•Some national guidelines: 9 months for PTB & 12 months for EPTB

•Most HIV-infected children respond to 6-month regimen

20102 •6-month regimen, then evaluate whether complete resolution has occurred

•If there is inadequate response continuation of therapy may be required

Variable3 Treatment failure,

aRR (95% CI)

p Relapse, aRR

(95% CI)

p Death during TB treat-

ment, aRR (95% CI)

p

Duration of rifampicin therapy

2 Months 1.3 (0.4-0.41) .67 3.6 (1.1-11.7) .14 1.8 (1.0-3.1) .03

6 Months 1.0 (0.4-2.8) 2.4 (0.8-7.4) 1.0 (0.6-1.6)

≥ 8 Months 1.0 (reference) 1.0 (reference) 1.0 (reference)

Intermittent therapy

Initial phase daily 1.0 (reference) .02 1.0 (reference) .002 1.0 (reference) .42

Initial phase thrice weekly 4.0 (1.5-10.4) 4.8 (1.8-12.8) 1.3 (0.7-2.3)

Receipt of ART

Some or all patients 1.0 (reference) .10 1.0 (reference) .21 1.0 (reference) .39

None or not started 3.8 (0.9-16.4) 3.5 (0.5-26) 0.8 (0.5-1.5)

Dispersion parameter for model 0.3 (-0.1 to 0.7) 0.22 (-0.04 to 0.53) 0.13 (-0.02 to 0.31)

1 WHO, WHO/HTM/TB/2006.361, 20062 WHO & IUATBLD, Guidance for national tuberculosis & HIV programmes, 2010 (near-final draft)3 Khan FA, et al. Clin Infect Dis 2010;50:1288-1299

Drug-resistant TB

• Prevalence of childhood MDR-TB is increasing1

• Treatment based on the approach in adults2

• MDR-TB: Optimal regimen & duration3

– Individualised regimens had higher treatment success [64%, CI: 59-68%] than standardised regimens [54%, CI: 43-68%]

• Outcome XDR-TB: 19% culture conversion rate, 70% within 6 months4

• Optimal dosing in drug-resistant TB?

• New drugs– TMC207 phase II RCT results5

– PA-824 [nitroimidazo-oxazine] and OPC-67683 [nitroimidazo-oxazole] are currently in clinical trials6

• Chemoprophylaxis efficacy trials?7

1 Schaaf HS, et al. Am J Public Health 2009;99:1486-14902 Chiang C-Y, et al. Int J Tuberc Lung Dis 2010;14:672-6823 Orenstein EW, et al. Lancet Infect Dis 2009;9:153-1614 Dheda K, et al. Lancet 2010;375:1798-1807

5 Diacon AH, et al N Engl J Med 2009;360:2397-24056 Ma Z, et al. Lancet 2010;375:2100-21097 Sneag DB, et al. Pediatr Infect Dis J 2007;26:1142-1146

Conclusions

• New global guidelines for treating children co-infected with HIV & TB are an improvement on previous recommendations and help to refocus the research agenda

• The applicability of these revised guidelines in South Africa should be established

• Priority research questions include:– Optimal duration of TB treatment

– Optimal doses of second-line drugs